Tuesday, June 16, 2009

Residual Solvent Analysis According to USP <467>

•“ Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used in the manufacture of drug substances and impurities or excipients, or in the preparation of drug products
•Residual solvents refers to the amount not removed during the purification of the product
•Residual solvents are one of the three main types of impurities in pharmaceutical articles (other two: organic and inorganic impurities)
•Residual solvents need to be controlled (ICH, USP, EP) and control is enforced (e.g., FDA)
USP Requirements

•All drug substances, excipients, and drug products (dosage forms) are subject to relevant control of residual solvents, even when no test is specified in the individual monograph
•Acceptable limits depend on solvent classification(toxicity, consistent with risk based approach)
•USP incorporates ICH Q3C classification and evaluation system and EP procedures
•Requirements aligned with ICH Q3C
•Testing is to be performed only for solvents “likely to be present”
–Used or produced in the final manufacturing step
–Used in previous steps and not removed by validated procedure
–Important for suppliers to disclose solvents (and manufacturing process)
•Limits for acceptable concentrations listed in the chapter are for drug products NOT for its components
•Quantitative or limit tests
•The concentration in the drug product may be
–Calculated from the contributions of components
–Determined experimentally; mandatory if:
–Solvents are used in its manufacture
–Cumulative calculation exceeds limits
•Manufacturers of drug products may rely on data provided by the suppliers of components
•The procedures described in this general chapter are to be applied whenever possible.Otherwise other methods can be used
Main changes to previous USP revision

•Title change: From “Organic Volatile Impurities (OVI)” to residual solvents
•Largely refer to ICH QC3 terminology, solvent categories and acceptance criteria
•Widely harmonized with EP
•Individual test procedures in Monographs replaced by general chapter <467>
•Finished product testing may not be necessary (testing of APIs and excipents may be enough)

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